This invention relates to dissolution testing and, in particular, to sampling and sample handling methods and apparatus suitable for use in pharmaceutical product dissolution testing.
Dissolution testing and apparatus for performing such testing are known in the art. U.S. Pat. No. 4,279,860 (Smolen) and U.S. Pat. No. 4,335,438 (Smolen) provide descriptions of the art of dissolution testing. In general, dissolution testing is used to determine the rate of dissolution of a material in a solution. For example, dissolution testing may be used to determine the rate of dissolution of pharmaceuticals in dosage form in specific test solutions to simulate digestion in a human. Requirements for such dissolution testing apparatus are provided in United States Pharmacopeia (USP), Section 711, Dissolution (2000).
Conventional apparatus for dissolution testing of pharmaceutical products includes a dissolution unit having several dissolution vessels, in each of which a test solution and a dosage to be tested, such as a tablet, may be placed. After a dosage to be tested is placed in a test solution in a dissolution vessel, a stirring element in the test solution is rotated at a specified rate for a specified duration. An example of such a dissolution unit is shown in U.S. Pat. No. 5,589,649 to Brinker et al. Samples of the test solution may be withdrawn from the dissolution vessels at various times and delivered to an instrument for analysis to determine the degree of dissolution of the dosages as a function of time.
Dissolution testing of a product typically requires data from a number of dosages of the product, and requires analysis of measured volumes of test solution samples withdrawn at a number of different times for each dosage being tested. Systems commonly referred to as “samplers” have been developed to automate various aspects of the process of withdrawing samples of test solution and conveying the withdrawn samples to an analytic instrument. In such systems, samples and other fluids are conveyed by pumps through tubing lines which are selected by valves. Samplers have been developed which can accommodate testing several (e.g., 6) dosages of a product at the same time, automatically withdrawing samples of test solution from each dissolution vessel at a number (e.g., 19) of specified times. Such samplers automatically deliver withdrawn samples to collection receptacles, such as test tubes or vials, for temporary storage prior to analysis. Samplers may also automatically transfer samples from the collection receptacles to an analytic instrument at an appropriate time for analysis.
Samplers typically include a rack that can hold an array of collection receptacles for storage of collected samples, and a head at which a set of tubing lines terminates, the lines each being connected to a pump which services a particular dissolution vessel. The head and the array of collection receptacles can be relatively moved and positioned with respect to one another so that a particular withdrawn sample can be delivered to a particular collection receptacle for storage. Dissolution testing systems may also include the ability to flush, wash, and purge the tubing lines, and to replace test solution withdrawn from the dissolution vessels with fresh test solution (“media replacement”) and/or a portion of the withdrawn test solution that is not delivered to the collection receptacles (“media recycling”).
The operation of the pumps and valves and the positioning of the head with respect to the collection receptacles in such a system may be controlled automatically by a programmable controller. Such a controller may be programmed to carry out a predetermined procedure to effect a particular dissolution test method.
Existing samplers have several shortcomings. For instance, they can accommodate only a single dissolution test method at a given time. Also, a collected sample may be stored in a collection receptacle that is capped by a septum, and it can be difficult to deliver a sample to such a collection receptacle. For instance, delivering a sample whose volume is an appreciable fraction of the collection receptacle volume can generate a high pressure in the collection receptacle. Further, fluid leaks and spills may occur in a sampler, which can damage the equipment and can render dissolution test results invalid.